Over time and with repeated administration many drugs of abuse will cause physical dependence that is expressed by a withdrawal syndrome when the drug is removed from the system. How drug effects lead to long lasting changes in the brain responsible for the addiction process is not well understood. Signaling via cAMP has been shown to be critical in the responses of a variety of drugs of abuse. The CREB (cAMP response element binding) protein has been identified as an important factor mediating a transcriptional response to elevated levels of cAMP and Ca2+. Using the techniques of gene targeting, mice have been generated which carry a mutation in the CREB gene. These mice exhibit a dramatically reduced withdrawal response following chronic morphine providing evidence that CREB is involved in physical opioid dependence. The overall goal of this research program is to evaluate the role of CREB in drug induced biochemical and behavioral changes in mice. In Specific Aim 1 we will analyze upstream components of the cAMP/PKA/CREB pathway in wild type and CREB deficient mice to characterize additional biochemical changes in cell signaling processes after deletion of the CREB protein that may be associated with behavioral actions of drugs of abuse. Abnormalities in the development of tolerance or rewarding properties may contribute to the reduction of naloxone precipitated withdrawal after chronic morphine in CREB mutant mice. In Specific Aim 2 we will evaluate the role of CREB in the development of tolerance and conditioned place preference to morphine using CREB mutant mice. A second member of the CREB/ATF family of transcription factors, namely CREM, is capable of substituting for many of the effects of CREB. In Specific Aim 3 we will characterize the role of CREM in the development of tolerance, dependence and withdrawal following chronic morphine. In Specific Aim 4, we will determine whether CREB or CREM has a more universal role in other forms of drug addiction by examining the induction and development of behavioral sensitization following cocaine in CREB and CREM mutant mice. The use of the above mouse models in the research program described here represent a definitive step to clarifying the molecular basis for the biochemical and behavioral changes involved in drug addiction. The complete understanding of these neurobiological mechanisms would open new perspectives for the future development of a more rational therapy for drug addiction.